Intercalation is one of several modes by which drugs interact with DNA wherein a planar portion of the drug is inserted in between adjacent stacked base pairs of a double stranded DNA. The intercalation process results in helix extension and unwinding of the DNA. Included within these drugs are antitumor agents, actinomycin D, adriamycin and daunomycin, as well as several drugs for treatment of parasitic disease including ethidium bromide, quinacrine, chloroquine and miracil D. U.S. Pat. No. 2,441,665 discloses a class of alkylene diamine derivatives which are valuable as antimalarial agents. U.S. Pat. No. 2,113,357 discloses basically substituted amino-acridine derivatives useful in treating blood parasites.
DNA intercalating ligands have been proposed for use in targeting alkylating agents to DNA by attachment of the intercalating ligand to the alkylating agent (Gourdie, et al. (1991) J. Med. Chem. 34:240-248). Since the biological properties of these DNA intercalating drugs are believed to result from their binding, efforts have focused on designing molecules that have a high affinity for DNA. Planar polycyclic aromatic molecules show a strong propensity to bind to DNA by intercalation (Jaycox, et al. (1987) J. Heterocyclic Chem. 24:1405-1408). To identify molecules with a greater affinity and selectivity for DNA, bifunctional intercalating agents in which two intercalating ligands are bridged by a central linking chain have been developed, wherein enhanced binding has been observed with molecules of this type (Canellakis, et al. (1976) Biochim. Biophys. Acta 418:277; Becker & Dervan (1979) J. Am. Chem. Soc. 101:3664; Wakelin, et al. (1986) Med. Res. Rev. 6:275). However, the chemical and physical nature of the linking chain has been found to play a role in the binding process.
For example, bis-intercalators bridged by flexible chains generally exhibit reduced affinities for DNA, in part because of self-stacking interactions which compete with the binding process (Barbet, et al. (1976) Biochemistry 15:2642; Capelle, et al. (1979) Biochemistry 18:3354). Further, bis-intercalation can introduce undesirable entropic effects when a flexible linker is forced into an extended chain conformation (Jaycox, et al. (1987) J. Heterocyclic Chem. 24:1405-1408). In addition, it is a concern that flexible bis-intercalators can creep in a stepwise fashion along the DNA macromolecule, thereby lowering ligand residence lifetimes at any one site (Denny, et al. (1985) J. Med. Chem. 28:1568). Such a process could have significant effects on efficacy of these intercalators as anticancer agents as residence lifetimes have been correlated with in vivo antitumor activity for a large number of DNA intercalators (Feigon, et al. (1984) J. Med. Chem. 27:450). Rigid tethers have been suggested as an (Jaycox, et al. (1987) J. Heterocyclic Chem. 24:1405-1408; U.S. Pat. No. 6,187,787).